The following processes for the preparation of optically active 2-[6-(substituted alkyl)-1,3-dioxane-4-yl]acetic acid derivatives represented by the above formula (I) are well known in the prior art.
(1) The process for the synthesis of optically active 2-[6-(hydroxy methyl)-1,3-dioxane-4-yl] acetic acid derivatives from 3-hydroxy--butylollactone via 3,5-dihydroxyhexane acid ester derivatives (Japanese Laid Open Patent Publication No. (Hei)4-173767).
(2) The process for the synthesis of optically active 2-[6-(cyano methyl)-1,3-dioxane-4-yl]acetic acid derivatives from 3-hydroxy-4-bromoester (U.S. Pat. No. 5,155,251).
(3) The process for the synthesis of 3,5,6-trihydroxyhexane acid ester derivatives from 4-chloroacetic acid ester through transforming to benzyloxy derivatives, reducing and chain-extending (Japanese Laid Open Patent Publication No. (Hei)6-65226).
(4) The process for the synthesis of optically active 2-[6-(substituted alkyl)-1,3-dioxane-4-yl] acetic acid derivatives from 4-chloro-3-hudroxybutyric acid ester through chain-extending and reducing, etc. (U.S. Pat. No. 5,278,313).
(5) The process for the synthesis of 3,5,6-trihydroxyhexane acid ester derivatives from malic acid via 2,4-dihydroxyadipic acid derivatives (Japanese Laid Open Patent Publication No. (Hei)4-69355).
However, since the aforementioned comprise the reactions under extremely low temperature such as around −80° C. (Processes 1, 2, 4 and 5) or the reaction of hydrogenation under the high pressure of 100 k/cm2 (Process 3), they should need a particular device for the reaction. Further, the processes use a high-priced reagent such as LDA in a part of steps or others, and the starting materials used can hardly produce various derivatives or need other operations and thus have a problem to require a long reaction course. Conclusively, any one of the processes cannot be effective in the commercial scale.
On the other hand, Korean Laid Open Patent Publication No. 2001-30819 (corresponding to PCT/JP1999/04299) has disclosed a process for preparing 2-[6-(substituted methyl)-1,3-dioxane-4-yl] acetic acid derivatives from low-cost materials without the need of a particular device such as a device for extremely low temperature reaction. However, the process give rise to problems of the purification of the final diol-based compounds and industrialization since it includes a stage of producing optically active diol compounds by use of microbial strands as a key step. Besides the aforementioned process can hardly produce various derivatives because of employing microbial strands.
The Statin-type pharmaceuticals such as Atrovastatin and Fluvastatin include compounds with optically active 1,3-diol unit. Therefore, there is a continuing need for a low-cost and simple process for preparing compounds comprising optically active 1,3-diol unit as a chiral building block, e.g., optically active 2-[6-(substituted alkyl)-1,3-dioxane-4-yl] acetic acid derivatives.
We have endeavored to solve the above issue. As a result, we have discovered that the optically active 2-[6-(substituted alkyl)-1,3-dioxane-4-yl] acetic acid derivatives of the following formula (I) could be produced efficiently according to a scheme which had not been publicly known. In the course of the above study, we have also discovered that a new process for producing β-hydroxyepoxycarboxylic acid derivative of formula (II) as other intermediates for preparing various compounds of formula (I) can be developed.
wherein R1 denotes a hydrogen atom, alkyl, aryl or alkylaryl, preferably methyl, ethyl, isopropyl, or tert-butyl, R2 and R3 which can be identical or different, denote a lower alkyl or phenyl and are capable of forming a six-membered ring, R4 stands for hydroxy, amino, alkylamino, arylamino, azido, cyano, halogeno, aryloxy, alkyloxy, arylalkyloxy, alkyl, alkenyl, aryl, or aminomethyl, etc.
In addition, we have discovered a method for preparing various compounds of formula (I) by reacting β-hydroxyepoxycarboxylic acid derivative of formula (II) with various nucleophilic reagents.
Therefore, it is a first object of the present invention to provide a process for preparing the compound of formula (I).
It is a second object of the invention to provide a process for preparing the compound of formula (II) as the intermediate to produce the compound of formula (I).